Nu-substituted-3-azabicyclooctanes [3: 3: 0] and salts thereof



6 2,962,496 Ce PatentedNov. 29, 1960 and- 'bisquaternary salts, of thesebases are shown by Formulae 3(a) and 3(1)) respectively;

2,962,496 N-SUBSTITUTED-S-AZABICYCLOOCTANES 35:0

i i AND SALTS THEREOF A-(CH )n-l:t=R Charles H. Grogan, Falls Church,V3,, and Leonard M. T Rice, Baltimore, Md., assignors, toThe.Gesclnckter FORMULA Fundfor Medical.Research,.Inc., Washmgton, D.C.,,a ia anthem" .n corporation of New York tr/ 2 NoDraw ing. Filed Jan. 28,1957, Ser. No. 636,511 2).n-N Aj -CHa)'n.-I;=VR.

11 Claims. ((11. 260-2475) R I Formula 3(a) Formula 3(0) In theseformulae A represents the azabicyclooctane nucleus and n a number-fromlto 6.1 .R represents two alkyl groups with from 1 to-6 ,carbon atoms. Rrepreof cardio-vascular and other diseases. More specifically sents an kl up i h f 1 t 6 a bon atoms, an. the inventionrelates toazabicyclooctane [3:3z0] bases, alkenyl group containing 3 to 6 carbonatoms s ch as and the acid ad n and and bis-quaternary the alkyl groupor the, structure (N=R) may represent salts thereof. a heterocyclic ringnamely, morpholine, piperidine, pyr:=. It is a basic Object of thePresent invention to Provide rolidine, piperazine or N-methylpiperazine, xrepresents. HOVelOIganic compounds and methods for-their Pp an anion such as chloride, iodide, bromide, acetate, sul.-, tion..fate, hydrogen sultate, methyl sulfate, toluene. sulfate,

If is another Object of the invention to P v novel, mucate, ortheophyllinate, The ,site of .both acid addi.-. physiologically activeCOHIPOIIBdS haying chemothel'fltion and quaternary. saltformationonfthe. nucleus A is. Peutic of medicinal P P Particularly ypalways the ring nitrogen at position 3. In the quaternary, activity.salts R' may be thesame as ordiflerent from R in any It is a furtherobject of the invention to provide novel of h f l i compounds comprisingN-dialkylaminoalkylabicyclo- The free bases, Formula-,1, andstheiracidaddition. octane [3:330] bases and N-hCtEl'ObYCliCflIlllllOalkyl-3-salts; Formula 2, possess varying, degpe es of antihistaazabicyclooctane[313:0] bases, and the acid addition, i i d bronchiodilatory a tivity. IThe quat rnary Q- and bis-quaternary Salts of these bases n fi salts ofthese bases, Formulae 3(a), 3(b), and in par 055 Of synthesizing theseCompoundsticular the bisquaternary salts, Formulaib), possess These andother objects andthe manner in which they a k d hypotensiyg aptiyity i lF are accomplished will become apparentto those con- I ample thedimethiodide f Examph 1 had a very f v rs nt t the art from the wls l ifi l pfi n 0f 1 able therapeutic ratio; At a total dosagefilevel of 25the general class of compounds and 'certainspecific ex- I M the was amarked lowering of bloodpressure ampllis of Particular members as Wellas general and at the same time the toxicity has beendetermined specificmethods for their synthesis. 40 to be over 500 mg./ kg. GenerallyStated, the novel Compounds discovered P In the process of preparing thebases of the invention, obtained by forming the N-dialkylaminoalkylimides 0 7 the iimides, ,usednasflstarting materialsumaybe. preparedN-heterocyclicarnino alkyl imides from the anhydride of: according t thprocess outlin d in ou o e ding apflcy p dicarboxylie acid, e reductionof plication, Serial No. 634,469; now U.S. Patent No. these l'mldes ySuitable "means to y ami 2,904,548, filed'of even date'herewith; whereinthe N'" alkyl-3-Budweycloocttme 3 6 777 ?N- srocyclicaminodialkylarninoalkyl imides. and heterocyclicaminoalky iialkyl-3-azablcyclooctane bases which y be Converted imides of1,2=cis-cyclopentane dicarboxylic anhydride by appropriate means intothe acid addition, monoand are d ib d d l i d, bis-quaternary salts.Formula I shows the general struc- Th following examples f ifi compoundsd tural formula of compounds obtainedby the methods methods willillustrate the manner in which the general hereafter more P F ydescribed-i synthesizing procedure maybe appliedto obtain particularmembers of the class of compounds discovered. H It will be understood,however, that the following ex- (Ere-CH1 amples are merely illustrativeand. are not, nor are they H2O N intended to be, exhaustive of all, the.compounds ,em-

\ EF braced by the present invention.

This invention relates to,organiochemoatherapeutic 15 agents and methodsof their preparation, and more particularly relates to .compounds of,valuew in the treatment Example l.N-dimethylaminoethyl-3 aiabicyclo[33:0] A octane, acid addition salts and ,quatsernarysalts t THE FREEBASE,

24.5 grams of the dimethylaminoethyl imide. of 1,2; ciscyclopentanedicarboxylic anhydride, dissolved in200; venience in representation theazabicyclooctane nucleus ml. of anhydrous ether was added-to-a rapidlystirred (enclosed in parenthesis, Formula 1) will be designated solutionof 15 g. of lithium aluminum hydride(LiAlH;;) by the letter A hereafter.in 600 ml. of anhydrous ethyl ether. Addition was made The acid additionsalts of the bases -illustrated-by so as to just maintain reflux.The-mixturewas'stirre Formulal are shown by Formula 2--while the monofor2 hours after all the imide solution had been added? FORMULA 1 Thisformula depicts the free bases, and for conallowed to stand overnightand then decomposed by the dropwise addition of water so that reflux wasjust maintained. When the evolution of hydrogen had ceased, a slightexcess of water was added, the mixture stirred 4 Ioniciodide.--Calculated-5 1 .3 5 Found-51.11%

Example III.-N-dimethylaminopropyl-3-azabicyclo [33:0] octane, acidaddition and quaternary salts 1-3 hours, inorganic material filtered oiland the residue 5 THE FREE BASE washed several times with ether. Theethereal filtrate was dried over anhydrous sodium sulfate, the ether 0f28 grams of aPPIPPYIate lmlde l stripped oil and the residue vacuumdistilled to yield 14 15 of hthmm a1,1mmum hydnde (LIAIHF) as detalledgrams of colorless liquid with an amine-like odor, B.P. under Efample IWelded 20 grams of the hue base 93-95 c./10.0 mm.: nD =l.4755 102-104mm,

Analysis Percent Percent Percent A al t P r ent Per ent Percent CarbonHydrogen Nitrogen Oarb on Hydrogen Nitrogen Calculated 72.47 12.16 15.37Calculated 73.41 12.32 14.27 Found 72. 41 12- 32 15- 43 Found 73. 70 12.28 14. 46

THE DIHYDROCHLORIDE THE DIHYDROCHLORIDE The base was dissolved inanhydrous isopropanol and an excess of an alcoholic solution of HCl gaswas added. Addmon of excess alcohohc-Hcl to the base m 80pm- On coolingand adding anhydrous ethyl ether, the dihydrochloride separated ascrystalline white material with a melting point at 296-298 C.

THE DIMETHIODIDE Ionic ch loride.--Calculated-27.78 Found When the basewas mixed with an excess of methyl iodide in anhydrous methanol andallowed to stand, the crystalline material crystallizing or precipitatedout on adding anhydrous ether was generally a mixture of the monoand dimethiodides. In order to obtain the dimethiodide free of monomethiodide,it was necessary to reflux the base with an excess of methyl iodide inanhydrous methanol 2-4 hours. The material that crystallized on coolingor on the addition of ether to the cooled reaction mixture melted at235-238 C. On recrystallization from ethanol it melted at 236-237" C.

Ionic i0dide.--Calculated-54.45%. Found-5428%.

Example Il.-N-diethylaminoethyl-3-azabicyclo [33:0] octane, acidaddition and quaternary salts THE FREE BASE 0n reduction of thediethylaminoethyl imide with lithium aluminum hydride (LiAlH in a mannersimilar to that described under Example I, 9 grams of the imide yielded7 grams of the title base of Example II, with B.P. 59-63/0.08 mm.: n=1.4757.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 74.22 12. 46 13. 32 Found 74. 55 12. 16 12. 94

THE DIHYDROCHLORIDE Addition of an excess of a saturated solution of HClin ethanol to the base dissolved in isopropanol, cooling and addition ofether produced the white crystalline dihydrochloride, M.P. 208-210 C.Recrystallization from isopropanol gave M.P. 210-2ll C.

Ionic chloride.-Calculated-25 .03 24.83%.

Found- THE DIMETHIODIDE panol and precipitation with ether yielded thesalt with M.P. 260-262 C. Recrystallization from isopropanolether gaveM.P. 261-262 C.

Ionic chloride.-Calculated-26.3 3 26.20%.

Found- THE DIMETHIODIDE The dimethiodide formed readily with excessmethyl iodide and the base in acetone at room temperature on standing 1day, M.P. 255-256 C. Recrystallization from isopropanol-ether gave M.P.256-257 C.

Ionic iodide.-Calculated52.85%. Found52.97%.

Example IV.-N-diethylaminopropyl-3-azabicyclo [33:0] octane, acidaddition salts and quaternary salts THE FREE BASE Reduction of thecorresponding imide (10 grams) with lithium aluminum hydride (LiAlI-I (6grams) as detailed in Example 1 yielded 7.4 grams of the title base,

THE DIHYDROCHLORIDE This was formed analogous to Example III, M.P.204-205 C. with no change on recrystallization from isopropanol-ether.

Ionic chloride.Calculated-23 23.53%.

Found- THE DIMETHIODHDE This was also formed analogous to Example III,M.P. 201-203 C. Recrystallization from isopropanol-ether, M.P. 208-210"C.

Ionic iodide.-Calculated-49.94% Found-49.88%.

Example V.-N-m0rpholinopr0pyl-3-azabicyclo [3.13:0] octane, acidaddition salts and quaternary salts THE FREE BASE 15 grams of the imidereduced with 6 grams of lithium aluminum hydride (LiAlH as detailedunder Example I, yielded 11 grams of the base, B.P. 94-98" C./O.1 mm, n=1.4957.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated-.-"70. 54 10. 99 ll. 75 Found 70. 74 11. 01 ll. 99

THE DIHYDROCHLORIDE This was formed analogous to Example III, M.P.265267 C., with no change on recrystallization.

Ionic ch loria'e.Calcu1ated-22.78 Found- THE DIMETHIODIDE This wasformed analogous to Example III, MP. 230- 232 C. with decomposition.Recrystallization from ethanol, M.P. 234-236 C., with decomposition.

Ionic i0dide.Calculated-48.01%. Found-48.48%.

While the preparation of the dihydrochloride acid addition salt has beenillustrated in the examples, other acid addition salts such as thehydrobromide, hydroiodide, acetate, sulfate, mucate and theophyllinatemay be prepared by combining the base with the required acid in a mannersimilar to the illustrated preparation of the dihydrochloride.

Similarly, while the preparation of the methiodide quaternary salt hasbeen illustrated in the examples, other mono and di-quaternary saltssuch as the methochloride, methobromide, dimetho-sulfate, metho-hydrogensulfate, and metho-toluene sulfate may be prepared in a manner similarto the illustrated preparation of the methiodide.

To form the quaternary salts where the anion is acetate, mucate,theophyllinate and other weak acid anions, the quaternary halide may befirst formed and then treated with silver oxide or an ion exchange resinto remove the halide. The free quaternary base hydroxide is nextneutralized with the appropriate weak acid such as acetic, mucic,theophyllin, etc.

From the foregoing description of a novel class of compounds, and thedetailed preparation and characterization of exemplary members of theclass, it will be understood that, on the basis of the discovery andknowledge disclosed herein, other specific compounds can be made andvariations in the methods of synthesis resorted to. The following tablecontains additional examples of bases prepared by the proceduresdetailed herein.

N-substituted-3-azabicycl0octanes [3 :3 0]

N-substituent:

N-diethylaminohexyl B.P. 111-117 C. at 0.3 mm.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 76.62 12. 86 10. 52 Found 76. 83 12. 73 10. 48

N-dihexylaminoethyl B.P. 117-125 C. at 0.08 mm. 50

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 78.19 13. 13 8. 68 Found 78. 28 12. 98 8. 76

N-piper1d1noethylB.P. 124-131" C. at 0.2 mm.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 75.62 11. 79 12. 59 Found 75. 58 11. 83 12. 44

N-pyrrolidinoethyl B.P. 118125 C. at 0.2 mm.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 74.94 11.61 13. 45 Found 74. 91 11. 57 13. 25

Therefore, the specific compounds and methods disclosed herein are to beconsidered in all respects as illustrative and not restrictive, thescope of the discovery being indicated by the appended claims ratherthan the foregoing descriptive detailed examples, and all specificcompounds and variations and methods which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

What is claimed and desired to be secured by the United States LettersPatent is:

1. As a novel composition of matter, a compound selected from the groupconsisting of (1) N-substituted derivatives of 3-azabicyclooctane[3:310] having the general formula where, in said formula, n is a numberfrom 1 to 6, R is selected from the group consisting of two alkyl groupseach alkyl group having 1 to 6 carbon atoms and radicals which form,together with the nitrogen atom to which they are attached, heterocyclicgroups consisting of morpholino, piperidino, piperazino,methyl-piperazino and pyrrolidino, and (2) the non-toxic acid additionsalts and a member selected from the group consisting of the lower alkylwith from 1 to 6 carbon atoms and the lower alkenyl with from 3 to 6carbon atoms mono and di quaternary salts of (1).

2. As a novel composition of matter, a dimethonium salt ofN-dimethylaminoethyl-3-azabicyclooctane [3:320].

3. As a novel composition of matter, a dimethonium salt ofN-diethylaminoethyl-3-azabicyclooctane [3:320].

4. As a novel composition of matter, a dimethonium salt ofN-dimethylaminopropyl 3 azabicyclooctane [3:3:0].

5. As a novel composition of matter, a dimethonium salt ofN-diethylaminopropyl-3-azabicyclooctane [3:3z0].

6. As a novel composition of matter, a dimethonium salt ofN-morpholinopropyl-3-azabicyclooctane [3:3z0].

7. As a novel composition of matter,N-dimethylaminoethyl-3-azabicyclooctane [3 :3 :0]

8. As a novel composition of matter, the dimethonium chloride ofN-dimethylaminoethyl 3 azabicyclooctane [3:3:0].

9. As a novel composition of matter, N-dimethylaminopropyl-3-azabicyclooctane [3:3 :0]

10. As a novel composition of matter, the dimethonium chloride ofN-dimethylaminopropyl-3-azabicyclooctane [3:3z0].

11. As a novel composition of matter,N-diethylaminoethyl-3-azabicyclooctane [3 :3 :0]

References Cited in the file of this patent UNITED STATES PATENTS2,541,211 Cusic et a1. Feb. 13, 1951 2,743,270 Blicke Apr. 24, 19562,745,836 Suter May 15, 1956 2,784,199 Grogan et a1 Mar. 5, 19572,786,834 Rice et al. Mar. 26, 1957 2,802,003 Grogan Aug. 6, 1957FOREIGN PATENTS 1,108,117 France Aug. 24, 1955 OTHER REFERENCES Richter:Organic Chemistry, vol. 3 (1923 pp. 3 and 4.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No.2,962,496 November 29, 1960 Charles H. Grogan et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 1, lines 53 to 58, the formula should appear as shown belowinstead of as in the patent:-

omd-om H20 N (CHZ)7LN=R \CHP OH2 H A column 2, line 20, for alkyl read-allyl; line 62, for oiscyclopentane read -ciscyclopentane-5 column 3,line 24, strike out the heading THE DIMETHIODIDE and insert the samefollowing lines 26 and 27 column 6, lines 15 to 20, the formula shouldappear as shown below instead of as in the patent:

Signed and sealed this 11th day of July 1961.

Attest:

ERNEST W. SWIDER, DAVID L. LADD,

Attesting Ofiioer. Commissioner of Patents.

1. AS A NOVEL COMPOSITION OF MATTER, A COMPOUND SELECTED FROM THE GROUPCONSISTING OF (1) N-SUBSTITUTED DERIVATIVES OF 3-AZABICYCLOOCTANE(3:3:0) HAVING THE GENERAL FORMULA
 6. AS A NOVEL COMPOSITION OF MATTER,A DIMETHONIUM SALT OF N-MORPHOLINOPROPYL-3-AZABICYCLOOCTANE (3:3:0)